Sudden infant Death Syndrome (SIDS) accounts for 5-6000 deaths/year in the U.S. The cause of SIDS is not known, but it is widely accepted that infants dying of SIDS are hypoxic for some time before death. The absence of a cardiac or lung-related explanation for the hypoxia (low oxygen level) strongly suggests that the ability of the infant to respond to hypoxia is abnormal. The carotid chemoreceptors, which are the oxygen sensors that drive breathing responses to hypoxia, are not mature at birth, and take time to reset and develop full sensitivity after birth. Impairment or delay in this resetting of carotid chemoreceptor sensitivity after birth could render an infant unable to respond to hypoxic stress. Thus, understanding postnatal resetting of carotid chemoreceptor oxygen sensitivity may be important for understanding the pathogenesis of SIDS. However, little is known about chemoreceptor resetting. The main hypotheses driving this application are a) that postnatal carotid chemoreceptor resetting is due to an increase in sensitivity of the oxygen sensing cell of the carotid body, the type I cell; b) that oxygen tension regulates type-I cell resetting; and c) that perinatal changes in dopaminergic modulation may be the link between chemoreceptor resetting and oxygen tension. We will employ fluorescence imaging techniques to measure changes in intracellular calcium in isolated type-I cells as a marker for the cellular response to hypoxia. Aim 1 will profile type1 cell sensitivity to oxygen and other stimuli at birth and during postnatal maturation. These studies will yield a detailed picture of the postnatal development of type-I cell sensitivity, begin to localize the site of chemoreceptor resetting, and determine whether resetting is stimulus- specific. Aim 2 addresses the role of oxygen tension in type-I cell resetting. By measuring type-I cell sensitivity in rats reared under low oxygen conditions, we will test the hypothesis that perinatal or postnatal hypoxia impairs development of chemoreceptor function by interfering with resetting of type-1 cell sensitivity. A second goal of aim 2 is to develop an in vitro model of chemoreceptor cell resetting, based on our observation that type-I cells reset oxygen sensitivity in culture. We will use this system to explore mechanisms and modulators of oxygen sensitivity resetting. Aim 3 examines the cellular mechanisms by which resetting of type-I cell sensitivity takes place. Studies will focus on the role of dopamine, which is believed to be a major modulator of chemoreceptor resetting and may be the link between resetting and oxygen tension changes at birth. Understanding how carotid chemoreceptor oxygen sensitivity resets and develops during postnatal maturation will have broad implications for understanding disorders in which infants fail to respond to hypoxic challenge, including SIDS.